It is well documented that oncogenic products and growth signals alter metabolism of cancer cells. However, it is less well understood whether and how the metabolism adjustments of tumor cells feedback to affect tumor progression. It is also not well understood how cancer cells coordinate the alterations between two major metabolism pathways, glycolysis and glutaminolysis. We observed that that PKM2 localized to the cell nucleus. The nuclear PKM2 functions as a transcription co-activator to activate the gene transcription. More importantly, PKM2, a key glycolysis enzyme, functions as a protein kinase to phosphorylate stat3 at Y705 therefore activating gene transcription. Our experiments demonstrate that the protein kinase activity of PKM2 mediates the effects of PKM2 in promoting cell proliferation. In addition, our study revealed that PKM2 upregulates glutaminase expression, indicating a feedback loop between cancer cell metabolism and cell proliferation, and potential function of this glycolysis enzyme in coordinating the changes of both glycolysis and glutaminolysis. The goal of this proposed research project is to understand the role of PKM2 in tumor progression. We propose three specific aims to test our hypothesis that PKM2, a glycolysis enzyme, facilitates cell proliferation and tumor progression not only by adjusting glycolytic metabolites flow in favor of biosynthesis, but also by regulating the glutaminolysis. By acting at multiple different metabolism processes, PKM2 fulfill the role of coordinating metabolism alterations and cell proliferation during tumor progression. The experiments proposed in this project will first test whether PKM2 indeed activates glutaminolysis. Experiments proposed in the 2nd specific aim will address whether activation of glutaminolysis by PKM2 also occurs in vivo. In the specific aim 3, we will elucidate how the growth signals affect the function of PKM2 in activation of glutaminolysis. Our studies will ultimately be applied to the development of new strategies for cancer treatment.